tbuckley/cabot-search huggingface dataset:
MCT4 blockade increases the efficacy of immune checkpoint blockade
Authors: Nathalie Babl, Sonja-Maria Decking, Florian Voll, Michael Althammer, Ada Sala-Hojman, Roberta Ferretti, Clarissa Korf, Christian Schmidl, Lisa Schmidleithner, Benedikt Nerb, Carina Matos, Gudrun E Koehl, Peter Siska, Christina Bruss, Fabian Kellermeier, Katja Dettmer, Peter J Oefner, Marvin Wichland, Ines Ugele, Christopher Bohr, Wolfgang Herr, Shivapriya Ramaswamy, Timo Heinrich, Christian Herhaus, Marina Kreutz, Kathrin Renner
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background &amp; Aims Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance. Methods To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1). Results Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact. Conclusions These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.
Tisagenlecleucel vs. historical standard of care in children and young adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia
Authors: Arend v. Stackelberg, Katja Jäschke, Etienne Jousseaume, Corinna Templin, Ulli Jeratsch, Daniela Kosmides, Ingo Steffen, Nicola Gökbuget, Christina Peters
Journal: Leukemia (2023)

In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD ≤ 0.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS
Detection and localization of caries and hypomineralization on dental photographs with a vision transformer model
Authors: Marco Felsch, Ole Meyer, Anne Schlickenrieder, Paula Engels, Jule Schönewolf, Felicitas Zöllner, Roswitha Heinrich-Weltzien, Marc Hesenius, Reinhard Hickel, Volker Gruhn, Jan Kühnisch
Journal: npj Digital Medicine (2023)

Abstract Caries and molar-incisor hypomineralization (MIH) are among the most prevalent diseases worldwide and need to be reliably diagnosed. The use of dental photographs and artificial intelligence (AI) methods may potentially contribute to realizing accurate and automated diagnostic visual examinations in the future. Therefore, the present study aimed to develop an AI-based algorithm that can detect, classify and localize caries and MIH. This study included an image set of 18,179 anonymous photographs. Pixelwise image labeling was achieved by trained and calibrated annotators using the Computer Vision Annotation Tool (CVAT). All annotations were made according to standard methods and were independently checked by an experienced dentist. The entire image set was divided into training ( N = 16,679), validation ( N = 500) and test sets ( N = 1000). The AI-based algorithm was trained and finetuned over 250 epochs by using image augmentation and adapting a vision transformer network (SegFormer-B5). Statistics included the determination of the intersection over union (IoU), average precision (AP) and accuracy (ACC). The overall diagnostic performance in terms of IoU, AP and ACC were 0.959, 0.977 and 0.978 for the finetuned model, respectively. The corresponding data for the most relevant caries classes of non-cavitations (0.630, 0.813 and 0.990) and dentin cavities (0.692, 0.830, and 0.997) were found to be high. MIH-related demarcated opacity (0.672, 0.827, and 0.993) and atypical restoration (0.829, 0.902, and 0.999) showed similar results. Here, we report that the model achieves excellent precision for pixelwise detection and localization of caries and MIH. Nevertheless, the model needs to be further improved and externally validated.
The Other Side of the Waterfall
Authors: Satya Das
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Time to Treat the Climate and Nature Crisis as One Indivisible Global Health Emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: JAMA (2023)
Time to treat the climate and nature crisis as one indivisible global health emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: Neuro-Oncology (2023)
Hypotension in heart failure is less harmful if associated with high or increasing doses of heart failure medication: Insights from the Swedish Heart Failure Registry
Authors: Nicolas Girerd, Stefano Coiro, Lina Benson, Gianluigi Savarese, Ulf Dahlström, Patrick Rossignol, Lars H. Lund
Journal: European Journal of Heart Failure (2023)

Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). We studied HFrEF patients from the Swedish HF registry (2000-2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin-angiotensin system (RAS) inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92-0.93), which was less high risk under optimized RAS inhibitor and beta-blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04-1.17) or decreasing (HR 1.29, 95% CI 1.18-1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86-1.02). The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization.
Hepatic Cavernous Hemangioma Mimicking Malignancy on 18F-FDG PET/CT Imaging
Authors: Yuwei Zhang, Peipei Wang, Ximin Shi, Hongli Jing
Journal: Clinical Nuclear Medicine (2023)

Abstract A 65-year-old woman was referred to our hospital because of a liver lesion revealed by ultrasound and CT in an outside institution. 18 F-FDG PET/CT images revealed an FDG-avid lesion in the left lateral lobe of the liver. Malignancy cannot be excluded. A subsequent resection was performed to remove the lesion. Postoperative pathology was hepatic cavernous hemangioma. This case suggests that PET/CT findings of FDG-avid hepatic cavernous hemangioma could mimic malignancy.
Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models
Authors: Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou
Journal: Journal of Clinical Investigation (2023)

Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.
Preliminary investigation of a significant national Cryptosporidium exceedance in the United Kingdom, August 2023 and ongoing
Authors: Lewis Peake, Thomas Inns, Christopher Jarvis, Grace King, Hussein Rabie, Joan Henderson, Adrian Wensley, Reece Jarratt, Christopher Roberts, Christopher Williams, Oghogho Orife, Lynda Browning, Matthew Neilson, Caitlin McCarthy, Paul Millar, Nicola Love, Kristin Elwin, Guy Robinson, Trish Mannes, Nick Young, Rachel Chalmers, Richard Elson, Roberto Vivancos
Journal: Eurosurveillance (2023)

Routine laboratory surveillance has identified an unprecedented and ongoing exceedance of Cryptosporidium spp. across the United Kingdom, notably driven by C. hominis transmission, since 14 August 2023. Information from 477 reported cases in England and Wales, followed up with a standardised exposure questionnaire as of 25 September 2023, identified foreign travel in 250 (54%) of 463 respondents and swimming in 234 (66%) of 353 cases. A significant, common exposure has not yet been identified in first analyses.
Parent-Perceived Benefits and Harms Associated With Internet Use by Adolescent Offspring
Authors: Harry Graff Kimball, Francesca Fernandez, Kathleen Anne Moskowitz, Minji Kang, Lindsay M. Alexander, Kevin P. Conway, Kathleen Ries Merikangas, Giovanni Abrahão Salum, Michael Peter Milham
Journal: JAMA Network Open (2023)

Limited systematic information on familial factors and perception of the benefits and harms of internet use by youths is available. Much of the current research has been hampered by small nondiverse samples and limited information on key familial and offspring characteristics.To characterize parental perceptions and concerns about internet use associated with adolescent development, well-being, safety, family connectedness, and potential for problematic internet use.A 20-minute, English-language survey was developed with expert stakeholders using previously validated questionnaires and was conducted online between June 17 and July 5, 2022. Participants included 1005 parents of children and adolescents aged 9 to 15 years drawn from an online digital survey platform and calibrated for representation with post hoc weightings.Parent survey responses about family characteristics and internet use were used to compute Internet Addiction Test scores for parents and their offspring, Alabama Parenting Questionnaire scores, and an aggregate family connectedness score.The survey cohort of 1005 parents included 568 women (56.5%) and 437 men (43.5%) with a mean age (SD) of 39.5 (6.4) years. In terms of race and ethnicity, the most common categories included Black or African American (95 [9.5%]), Latinx or Hispanic (100 [10.0%]), White (602 [59.9%]), and 2 or more races or ethnicities (122 [12.1%]). Respondents endorsed parental concerns that included exposure to harmful content (646 [64.3%]) and online bullying (533 [53.0%]). Two hundred twenty-five parents (22.4%) had specific concerns about internet addiction in their adolescent offspring, and twice as many parents reported specific concerns about internet addiction than substance addiction. However, parents also indicated that internet use improved family connectedness among immediate families (468 [46.6%]) and extended families (568 [56.5%]). Internet Addiction Test scores in adolescent offspring were correlated with parent scores (β = 0.62 [SE = 0.02]; P < .001) and Alabama Parenting Questionnaire-Inconsistent Discipline scores (β = 0.23 [SE = 0.11]; P = .04).In this survey study of parent perceptions of internet use among adolescent offspring, parents believed the internet brought families closer yet also expressed concerns. Problematic internet use among youths was correlated with negative parenting styles and parent internet use. This research adds to the literature by suggesting that families, their communities, and industry may have common ground to collaborate on reducing the negative effects of internet use.
Genetic Predisposition to Elevated C-Reactive Protein and Risk of Obstructive Sleep Apnea
Authors: Tianyi Huang, Matthew Goodman, Heming Wang, Tamar Sofer, Shelley S. Tworoger, Meir J. Stampfer, Richa Saxena, Susan Redline
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Genetic Predisposition to Elevated C-Reactive Protein and Risk of Obstructive Sleep Apnea." American Journal of Respiratory and Critical Care Medicine, 209(3), pp. 329–331
Cold-Driven Hemoglobin Evolution in Antarctic Notothenioid Fishes Prior to Hemoglobin Gene Loss in White-Blooded Icefishes
Authors: Thomas Desvignes, Iliana Bista, Karina Herrera, Audrey Landes, John H Postlethwait
Journal: Molecular Biology and Evolution (2023)

Expression of multiple hemoglobin isoforms with differing physiochemical properties likely helps species adapt to different environmental and physiological conditions. Antarctic notothenioid fishes inhabit the icy Southern Ocean and display fewer hemoglobin isoforms, each with less affinity for oxygen than temperate relatives. Reduced hemoglobin multiplicity was proposed to result from relaxed selective pressure in the cold, thermally stable, and highly oxygenated Antarctic waters. These conditions also permitted the survival and diversification of white-blooded icefishes, the only vertebrates living without hemoglobin. To understand hemoglobin evolution during adaptation to freezing water, we analyzed hemoglobin genes from 36 notothenioid genome assemblies. Results showed that adaptation to frigid conditions shaped hemoglobin gene evolution by episodic diversifying selection concomitant with cold adaptation and by pervasive evolution in Antarctic notothenioids compared to temperate relatives, likely a continuing adaptation to Antarctic conditions. Analysis of hemoglobin gene expression in adult hematopoietic organs in various temperate and Antarctic species further revealed a switch in hemoglobin gene expression underlying hemoglobin multiplicity reduction in Antarctic fish, leading to a single hemoglobin isoform in adult plunderfishes and dragonfishes, the sister groups to icefishes. The predicted high hemoglobin multiplicity in Antarctic fish embryos based on transcriptomic data, however, raises questions about the molecular bases and physiological implications of diverse hemoglobin isoforms in embryos compared to adults. This analysis supports the hypothesis that the last common icefish ancestor was vulnerable to detrimental mutations affecting the single ancestral expressed alpha- and beta-globin gene pair, potentially predisposing their subsequent loss.
The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis
Authors: Scott M. Norberg, Ke Bai, Cem Sievers, Yvette Robbins, Jay Friedman, Xinping Yang, Meg Kenyon, Elizabeth Ward, Jeffrey Schlom, James Gulley, Amy Lankford, Roshanak Semnani, Helen Sabzevari, Douglas E. Brough, Clint T. Allen
Journal: Science Translational Medicine (2023)

Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11–specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10 , and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.
Menstruation Confounding the Correct Interpretation of 99mTc-RBC Bleeding Scan
Authors: Guanyun Wang, Xia Lu, Wei Wang, Jigang Yang
Journal: Clinical Nuclear Medicine (2023)

Abstract 99m Tc-RBC bleeding scan in a 17-year-old adolescent girl showed an increased focal activity in the pelvis. However, SPECT/CT showed that this activity was located in the uterus, which was considered a normal variant considering that the patient was in her fourth day of the menstrual period. Subsequent 99m TcO 4 − Meckel scan showed the typical characteristic of ectopic gastric mucosa in the small bowel. Postsurgical pathology confirmed the diagnosis of ectopic gastric mucosa. This case suggested the menstrual period uterus should be included as differential diagnosis of 99m Tc-RBC scan.
Time to Treat the Climate and Nature Crisis as One Indivisible Global Health Emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: JAMA Cardiology (2023)
Eligibility for Human Leukocyte Antigen–Based Therapeutics by Race and Ethnicity
Authors: Timothée Olivier, Alyson Haslam, Jordan Tuia, Vinay Prasad
Journal: JAMA Network Open (2023)

Importance The development of therapeutics for patients who are positive for specific human leukocyte antigen (HLA) subtypes evokes the question of whether certain racial and ethnic groups are more or less likely to be eligible for novel products. Objective To determine whether racial and ethnic inequities were present with regard to trial eligibility in trials investigating a therapeutic restricted to patients with specific HLA subtypes. Design, Setting, and Participants This cross-sectional study included all clinical trials registered in ClinicalTrials.gov through March 18, 2022, that investigated an interventional study of a therapeutic strategy and restricted participants to those with at least 1 HLA subtype. Data were analyzed from May 8 to July 1, 2022. Main Outcomes and Measures The type of therapeutics used in trials, the condition under study, the HLA subtypes used, and the likelihood of being enrolled in such a trial according to race and ethnicity. Results Of 2135 trials identified, 263 met inclusion criteria. Overall, the estimated likelihood of being eligible for an HLA-based trial was 50.3%. Individuals of African American descent had the lowest likelihood of eligibility (33.0%), while being an individual of European descent conferred the highest (53.0%; 1.6 times more likely than African American individuals). Most trials studied anticancer therapeutics (258 [98.1%; 95% CI, 96.4%-99.7%]), and most were a therapeutic vaccine (179 [68.1%; 95% CI, 62.4%-73.7%]). The HLA-A*02:01 allele and the HLA-A2 serotype were the most frequent HLA subtypes for trial eligibility. The frequency of the HLA-A*02:01 allele in the population varied, with 11.9% (95% CI, 11.8%-12.0%) in African or African American individuals and 27.1% (95% CI, 27.1%-27.1%) in individuals of European descent. Conclusions and Relevance The findings of this cross-sectional study suggest that enrollment restrictions for clinical trials investigating novel HLA therapeutics may be associated with racial and ethnic inequities with regard to trial eligibility. Overcoming these restrictions poses biological challenges, but solutions must be implemented to provide equal access to innovative strategies regardless of race or ethnicity.